Cycloimidamicins, Novel natural lead compounds for translation inhibition in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most concerning pathogenic bacteria. We screened antibiotics using a highly drug-sensitive P. aeruginosa strain and an oligotrophic medium, and successfully isolated novel antibiotics, namely cycloimidamicins (CIMs), from a rare actinomycete strain, Lentzea sp. MM249-143F7. X-ray and nuclear magnetic resonance analyses revealed that CIMs possess a distinctive and unprecedented molecular structure, containing tetramic acid and an imidazole ring bound directly to indolone. The CIMs exhibited potent antibacterial activity against Gram-negative bacteria, as well as translation inhibition in Escherichia coli in both intact cells and in vitro. Additionally, E. coli strains resistant to known translation inhibitors did not exhibit cross-resistance to CIMs, suggesting that CIMs inhibit bacterial growth by blocking translation through a novel mechanism.

Intensive Frequent Granulocyte Adsorptive Apheresis Therapy for Acute Fulminant Ulcerative Colitis: Two Consecutive Case Reports.

Granulocyte/monocyte adsorptive apheresis (GMA) therapy is a treatment method for ulcerative colitis (UC). Twice-weekly GMA regimens are usually administered to treat severe UC. Although GMA efficacy is considered frequency-dependent, there is no uniformly accepted optimal GMA regimen, and there is insufficient evidence regarding optimal GMA therapy frequency for acute fulminant UC. Case 1 was of a 33-year-old man, and case 2 was of a 20-year-old woman. They were diagnosed with acute fulminant UC and treated with steroid therapy, but exhibited exacerbated UC, and their conditions worsened. We, therefore, initiated intensive frequent GMA therapy (conducted 10-11 times during a 13-day period). In both cases, remission was achieved within two weeks of therapy induction. Herein, we describe two consecutive cases in which rapid remission of acute fulminant UC was achieved without adverse events using intensive frequent GMA therapy. These cases suggest that intensive frequent GMA therapy might induce rapid remission in acute fulminant UC cases and may be more effective than twice-weekly GMA regimens.

Concise Total Synthesis and Biological Evaluation of Pargamicin A and its Diastereomer, Piperazic Acid-containing Cyclopeptides.

We have accomplished the total synthesis, structure determination, and biological evaluation of pargamicin A and one of its diastereomers. Two key tripeptide segments were synthesized using a linear peptide elongation process that includes the direct coupling of a poorly nucleophilic piperazic acid derivative. The resulting tripeptides were coupled using triphosgene/collidine at ambient temperature leading to a precursor for the final cyclization step. T3P-promoted macrolactamization under high-dilution conditions, followed by the removal of the benzyl protecting group was used to furnish two putative structures of pargamicin A. Comparison of the 1 H and 13 C NMR spectra and the antibacterial activity of the natural and synthetic products successfully revealed that the absolute configuration of the N-hydroxy-Ile residue of pargamicin A is 2S,3S. A biological evaluation of synthetically obtained pargamicin A and its diastereomer suggested that the stereostructure of the cyclic peptide scaffold of the natural product plays a crucial role in determining the strength of its antibacterial activity.

Disseminated Bacillus Calmette-Guérin Infection with Rhabdomyolysis, Acute Kidney Injury, and Interstitial Pneumonia after Bacillus Calmette-Guérin Intravesical Instillation Therapy.

A 79-year-old man experienced a fever and immobility after receiving 6 doses of Bacillus Calmette-Guérin (BCG) intravesical instillation therapy for bladder tumor. Rhabdomyolysis and acute kidney injury occurred; therefore, hemodialysis was performed. His kidney function was restored. However, he exhibited an inflammatory reaction that was resistant to broad-spectrum antibiotics and eventually developed interstitial pneumonia. Corticosteroid treatment partially relieved the symptoms of interstitial pneumonia, although disuse syndrome persisted. He was diagnosed with disseminated BCG infection through sputum culture. BCG infection shows various symptoms and is difficult to diagnose microbiologically. It should be suspected when systemic symptoms occur after BCG intravesical instillation therapy.

Remission Induction of IgG4-related Membranous Nephropathy with Multitarget Therapy.

IgG4-related membranous nephropathy (MN) is often refractory to glucocorticoid (GC) therapy, and treatment remains unclear. We herein report a 67-year-old Japanese man with IgG4-related MN and tubulointerstitial nephritis. A post-gastroscopy antibody test revealed Helicobacter pylori infection. After eradication, his proteinuria decreased indefinitely. We started prednisolone (30 mg/day), long-term GCs, and immunosuppressant therapy. However, remission proved challenging to achieve, with persistent proteinuria present at 1.0-2.0 g/gCr. We performed multitarget therapy for refractory IgG4-related MN, achieving proteinuria remission (<0.3 g/gCr). Multitarget therapy with low-dose GCs can resolve refractory IgG4-related MN through remission induction of proteinuria and minimize the risks associated with GC therapy.

Hypertensive Anaphylaxis After Moderna COVID-19 Vaccination: A Case Report.

Hypotension after exposure to an allergen is a well-known indicator of an anaphylactic reaction. However, hypertensive anaphylaxis often goes unrecognized. Increased blood pressure can present as an anaphylactic reaction, which is called hypertensive anaphylaxis. A 48-year-old woman complained of a tickle sensation in the throat and dyspnea 30 minutes after being administered the first dose of the Moderna coronavirus disease 2019 (COVID-19) vaccine. The patient had no history of hypertension, anxiety, or panic disorder. Forty-five minutes after the vaccination, stridor was noted, and the patient developed severe hypertension with a blood pressure of 197/153 mmHg. The patient also had tachycardia, cervical angioedema, and nausea, which occurred in a short period of time, indicating type I hypersensitivity reaction, that is, an anaphylactic reaction. The patient was diagnosed with Brighton classification Level 1 anaphylaxis caused by COVID-19 vaccination. For managing the patient, two intramuscular adrenaline injections, famotidine, chlorpheniramine, metoclopramide, and methylprednisolone were administered via intravenous infusion. After the administration of medications, all symptoms resolved, and the blood pressure was reduced. Other differential diagnoses for increased blood pressure after vaccination were excluded; therefore, we concluded that this phenomenon of increased blood pressure was hypertensive anaphylaxis. Not only hypotension but also the acute onset of increased blood pressure after vaccination may occur as a premonitory symptom of anaphylaxis. In hypertensive anaphylaxis, both anaphylaxis and increased blood pressure can be treated with intramuscular adrenaline injection. Clinicians should be aware of the occurrence of hypertensive anaphylaxis.

Rediscovery of 4-Trehalosamine as a Biologically Stable, Mass-Producible, and Chemically Modifiable Trehalose Analog.

Nonreducing disaccharide trehalose is used as a stabilizer and humectant in various products and is a potential medicinal drug, showing curative effects on the animal models of various diseases. However, its use is limited as it is hydrolyzed by trehalase, a widely expressed enzyme in multiple organisms. Several trehalose analogs are prepared, including a microbial metabolite 4-trehalosamine, and their high biological stability is confirmed. For further analysis, 4-trehalosamine is selected as it shows high producibility. Compared with trehalose, 4-trehalosamine exhibits better or comparable protective activities and a high buffer capacity around the neutral pH. Another advantage of 4-trehalosamine is its chemical modifiability: simple reactions produce its various derivatives. Labeled probes and detergents are synthesized in one-pot reactions to exemplify the feasibility of their production, and their utility is confirmed for their respective applications. The labeled probes are used for mycobacterial staining. Although the derivative detergents can be effectively used in membrane protein research, long-chain detergents show 1000-3000-fold stronger autophagy-inducing activity in cultured cells than trehalose and are expected to become a drug lead and research reagent. These results indicate that 4-trehalosamine is a useful trehalose substitute for various purposes and a material to produce new useful derivative substances.

Isolation of new derivatives of the 20-membered macrodiolide bispolide from Kitasatospora sp. MG372-hF19.

New three macrocyclic diolides, named bispolides C-E (1-3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole glycoside and leptomycins as we reported previously. The absolute structures of compounds 1-3 were elucidated by NMR and X-ray crystallography. Compounds 1-3 diverge from the known nine bispolides in their different alkylation patterns on the 20-membered macrocyclic diolide skeleton and the side chain in their planar structures. Furthermore, compounds 1-3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci and cytotoxic activity against human cancer cell lines. Among them, compound 3 has the most potent biological activities against bacteria and tumor cells. Additionally, using a membrane-potential-sensitive fluorescence probe, we found that compounds 1-3 and elaiophylin have a similar effect on membrane potential in A549 human lung cancer cells.

Acute tubulointerstitial nephritis in a patient with early bronchial tuberculosis.

Patients with chronic kidney disease (CKD) are commonly at high risk of tuberculosis (TB). Conversely, TB rarely causes tubulointerstitial nephritis. A 75-year-old Japanese man who was undergoing periodic follow-ups for CKD stage G3aA3 with membranous nephropathy was diagnosed with acute kidney injury (AKI) (estimated glomerular filtration rate [eGFR]: 15 mL/min/1.73 m2) without prerenal AKI. He reported developing recent-onset cough 3 weeks prior to presenting to us. Renal biopsy revealed acute tubulointerstitial nephritis along with known membranous nephropathy. CD4+ helper T cells comprised most lymphocytes in the tubulointerstitium. Results of the interferon-gamma release assay, sputum smear test, polymerase chain reaction (PCR), and culture test were positive for TB. Chest computed tomography revealed thickening of the left bronchial wall; therefore, a diagnosis of early bronchial TB was made; his urine culture and PCR were negative for TB. At four months after TB treatment with no immunosuppressive therapy, his eGFR improved to 50 mL/min/1.73 m2, and based on this progress, the AKI was diagnosed as tuberculosis-associated tubulointerstitial nephritis (TATIN). Although TATIN typically occurs with chronic or miliary tuberculosis, it is very rare in early bronchial TB. Identification of TATIN is important in kidney diseases of unknown etiology, and treatment with anti-TB drugs is necessary.

Anti-neutrophil cytoplasmic antibody-associated vasculitis accompanied by type II heparin-induced thrombocytopenia resulting in asymptomatic cerebral infarction: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) involves platelet activation and aggregation caused by heparin or HIT antibodies associated with poor survival outcomes. We report a case of HIT that occurred after hemodialysis was started for rapidly progressive glomerulonephritis (RPGN), which was caused by anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), and ultimately resulted in asymptomatic cerebral infarction. CASE PRESENTATION: A 76-year-old Japanese man was urgently admitted to our hospital for weight loss and acute kidney injury (serum creatinine: 12 mg/dL). Hemodialysis therapy was started using heparin for anticoagulation. Blood testing revealed elevated titers of myeloperoxidase anti-neutrophil cytoplasmic antibodies, and renal biopsy revealed crescentic glomerulonephritis with broad hyalinization of most of the glomeruli and a pauci-immune staining pattern. These findings fulfilled the diagnostic criteria for microscopic polyangiitis, and the patient was diagnosed with RPGN caused by AAV. Steroid pulse therapy, intermittent pulse intravenous cyclophosphamide, and oral steroid therapy failed to improve the patient's renal function, and maintenance dialysis was started. However, on day 15, his platelet count had decreased to 47,000/µL, with clotting observed in the hemodialysis catheter. Magnetic resonance imaging of the head identified acute asymptomatic brain infarction in the left occipital lobe, and a positive HIT antibody test result supported a diagnosis of type II HIT. During hemodialysis, the anticoagulant treatment was changed from heparin to argatroban. Platelet counts subsequently normalized, and the patient was discharged. A negative HIT antibody test result was observed on day 622. CONCLUSIONS: There have been several similar reports of AAV and HIT co-existence. However, this is a rare case report on cerebral infarction with AAV and HIT co-existence. Autoimmune diseases are considered risk factors for HIT, and AAV may overlap with other systemic autoimmune diseases. To confirm the relationship between these two diseases, it is necessary to accumulate more information from future cases with AAV and HIT co-existence. If acute thrombocytopenia and clotting events are observed when heparin is used as an anticoagulant, type II HIT should always be considered in any patient due to its potentially fatal thrombotic complications.

Relationship Between Helicobacter pylori Infection and Arteriosclerosis.

It is reported that Helicobacter pylori (H. pylori) infection may be linked to non-digestive tract diseases, such as arteriosclerosis including dyslipidemia, diabetes, obesity, hypertension, and cardiovascular disease. Therefore, we reviewed recent studies available in PubMed dealing with the mechanisms of arteriosclerosis due to H. pylori infection and the effects of H. pylori eradication. Conventional studies suggested that H. pylori infection may increase the risk of arteriosclerosis. A large interventional study is required to clarify the causal relationships and the effects of bacterial eradication.

New chloptosins B and C from an Embleya strain exhibit synergistic activity against methicillin-resistant Staphylococcus aureus when combined with co-producing compound L-156,602.

Two new dimeric cyclohexapeptides, chloptosins B and C, were discovered from the culture broth of Embleya sp. MM621-AF10 together with the known compounds chloptosin and L-156,602. The structures of the new chloptosins were determined by spectroscopic studies and advanced Marfey's methods. The stereo structure of the constituent isoleucine was determined by C3 Marfey's analysis. Chloptosins demonstrated potent antimicrobial activity against Gram-positive bacteria including drug-resistant strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci with MICs of 0.5-2 µg ml-1. The antimicrobial activities of chloptosins were enhanced by addition of co-producing compound L-156,602, as shown by checkerboard analysis.

Health risk of travel for chronic kidney disease patients.

The number of people with chronic kidney disease (CKD) has increased and so has their demand for travel. However, the health risk posed by travel in these patients is unclear. Few reports document the travel risk in CKD and dialysis patients. The aim of this study is to summarize the existing evidence of the influence of travel on risks in CKD patients. We aim to describe the association between the impact of travel risks and patients with CKD. A detailed review of recent literature was performed by reviewing PubMed, Google Scholar, and Ichushi Web from the Japan Medical Abstracts Society. Screened involved the following keywords: "traveler's thrombosis," "venous thromboembolism," "deep vein thrombosis," "altitude sickness," "traveler's diarrhea," "jet lag syndrome," "melatonin," with "chronic kidney disease" only, or/and "dialysis." We present a narrative review summary of the literature from these screenings. The increased prevalence of thrombosis among travelers with CKD is related to a decrease in the estimated glomerular filtration rate and an increase in urine protein levels. CKD patients who remain at high altitudes are at an increased risk for progression of CKD, altitude sickness, and pulmonary edema. Traveler's diarrhea can become increasingly serious in patients with CKD because of decreased immunity. Microbial substitution colitis is also common in CKD patients. Moreover, time differences and disturbances in the circadian rhythm increase cardiovascular disease events for CKD patients. The existing literature shows that travel-related conditions pose an increased risk for patients with CKD.

Efficacy of High-Dose Mycophenolate Mofetil in Multitarget Therapy for Lupus Nephritis: Two Consecutive Case Reports.

The complete remission rate for lupus nephritis (LN) is higher with multitarget therapy (MT) using tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids than with steroid plus cyclophosphamide co-therapy. MT is also considered highly safe and is used to treat refractory LN. During MT, MMF is usually administered at a dose of 1 g/day similar to conventional MT; however, it remains unclear whether this is the optimal dose of MMF for Japanese patients, especially those refractories to conventional MT. We report two consecutive cases of refractory LN with conventional MT, case 1 was a 48-year-old woman with LN III (A) and nephrotic syndrome, and Case 2 was a 20-year-old man with LN IV-S (A), nephrotic syndrome, and acute kidney injury. LN was diagnosed by kidney biopsy. Because both these patients were refractory to conventional MT treatment (MMF at a dose of 1.0 g/day) for more than six months, MMF doses of 2.5 and 1.5-2.0 g/day were used as part of MT for cases 1 and 2, respectively. Increasing the MMF dose in MT to 1.5-2.5 g/day without increasing the steroid dose led to complete remission, without any recurrence, and allowed administration of a lower dose of a steroid such as prednisolone (5.5 ± 1.5 mg/day) 18 months after the MMF dose increase. The mean number of days from the start of the higher MMF dose of 1.5-2.5 g/day in MT to complete remission was 129.5 ± 10.5 days. Moreover, lymphopenia, hypogammaglobulinemia, gastrointestinal disturbances, or any infections were not observed as adverse events after increasing the MMF dose in MT. Thus, increasing MMF dose while maintaining the steroid dose in MT may induce complete remission; this will minimize the use of steroids in Japanese patients with refractory LN in conventional MT.

Non-urate transporter 1, non-glucose transporter member 9-related renal hypouricemia and acute renal failure accompanied by hyperbilirubinemia after anaerobic exercise: a case report.

BACKGROUND: Renal hypouricemia (RHUC) is an inherited heterogenous disorder caused by faulty urate reabsorption transporters in the renal proximal tubular cells. Anaerobic exercise may induce acute kidney injury in individuals with RHUC that is not caused by exertional rhabdomyolysis; it is called acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE). RHUC is the most important risk factor for ALPE. However, the mechanism of onset of ALPE in patients with RHUC has not been elucidated. The currently known genes responsible for RHUC are SLC22A12 and SLC2A9. CASE PRESENTATION: A 37-year-old man presented with loin pain after exercising. Despite having a healthy constitution from birth, biochemical examination revealed hypouricemia, with a uric acid (UA) level of < 1 mg/dL consistently at every health check. We detected acute kidney injury, with a creatinine (Cr) level of 4.1 mg/dL, and elevated bilirubin; hence, the patient was hospitalized. Computed tomography revealed no renal calculi, but bilateral renal swelling was noted. Magnetic resonance imaging detected cuneiform lesions, indicating bilateral renal ischemia. Fractional excretion values of sodium and UA were 0.61 and 50.5%, respectively. Urinary microscopy showed lack of tubular injury. The patient's older sister had hypouricemia. The patient was diagnosed with ALPE. Treatment with bed rest, fluid replacement, and nutrition therapy improved renal function and bilirubin levels, and the patient was discharged on day 5. Approximately 1 month after onset of ALPE, his Cr, UA, and TB levels were 0.98, 0.8, and 0.9 mg/dL, respectively. We suspected familial RHUC due to the hypouricemia and family history and performed genetic testing but did not find the typical genes responsible for RHUC. A full genetic analysis was opposed by the family. CONCLUSIONS: To the best of our knowledge, this is the first report of ALPE with hyperbilirubinemia. Bilirubin levels may become elevated as a result of heme oxygenase-1 activation, occurring in exercise-induced acute kidney injury in patients with RHUC; this phenomenon suggests renal ischemia-reperfusion injury. A new causative gene coding for a urate transporter may exist, and its identification would be useful to clarify the urate transport mechanism.

Successful management of visceral disseminated varicella zoster virus infection during treatment of membranous nephropathy: a case report.

BACKGROUND: Visceral disseminated varicella zoster virus (VDVZV) infection is a rare disease with a high mortality rate (55%) in immunocompromised patients, but it is not yet widely recognized in the field of nephrology. We report a case of VDVZV contracted during immunosuppressive therapy for membranous nephropathy. CASE PRESENTATION: A 36-year-old woman was diagnosed with membranous nephropathy and was being treated with immunosuppressive therapy consisting of 60 mg/day prednisolone, 150 mg/day mizoribine, and 150 mg/day cyclosporine. Nephrosis eased; therefore, the prednisolone dosage was reduced. However, 50 days after starting immunosuppressive therapy, the patient suddenly developed strong and spontaneous abdominal pain, predominantly in the epigastric area, without muscular guarding or rebound tenderness. Blood data indicated neutrophil-dominant elevated white blood cell count, reduced platelet count, elevated transaminase and lactate dehydrogenase, slightly increased C-reactive protein, and enhanced coagulability. Abdominal computed tomography revealed a mildly increased enhancement around the root of the superior mesenteric artery with no perforation, intestinal obstruction, or thrombosis. The cause of the abdominal pain was unknown, so the patient was carefully monitored and antibiotic agents and opioid analgesics administered. The following day, blisters appeared on the patient's skin, which were diagnosed as varicella. There was a marked increase in the blood concentration of VZV-DNA; therefore, the cause of the abdominal pain was diagnosed as VDVZV. Treatment with acyclovir and immunoglobulin was immediately started, and the immunosuppressive therapy dose reduced. The abdominal pain resolved rapidly, and the patient was discharged 1 week after symptom onset. DISCUSSIONS AND CONCLUSIONS: This patient was VZV-IgG positive, but developed VDVZV due to reinfection. Abdominal pain due to VDVZV precedes the skin rash, which makes it difficult to diagnose before the appearance of the rash, but measuring the VZV-DNA concentration in the blood may be effective. Saving the patient's life requires urgent administration of sufficient doses of acyclovir and reduced immunosuppressive therapy.

Focal segmental glomerulosclerosis lesion associated with inhibition of tyrosine kinases by lenvatinib: a case report.

BACKGROUND: Lenvatinib is a tyrosine kinase inhibitor with novel binding ability. It is considered the standard of care for metastatic thyroid cancer; moreover, whether it is indicated for other malignant tumors has been examined. Lenvatinib increases the risk of kidney injury in some patients. In comparison with sorafenib, which is a conventional tyrosine kinase inhibitor (TKI), lenvatinib results in more side effects, including hypertension and proteinuria. We describe a case of secondary focal segmental glomerulosclerosis (FSGS) that developed following treatment of metastatic thyroid cancer with lenvatinib and reviewed the mechanisms of renal impairment. CASE PRESENTATION: We describe a patient with metastatic thyroid cancer who developed hypertension, nephrotic syndrome, and acute kidney injury after 3 months of lenvatinib treatment. Renal biopsy results revealed that 7 of 16 glomeruli indicated complete hyalinization, and that the glomeruli with incomplete hyalinization showed FSGS due to a vascular endothelial disorder and podocyte damage, which seemed to have been induced by lenvatinib treatment. These findings were similar to those of renal impairment treated with conventional TKIs. Although lenvatinib treatment was discontinued, up to 15 months were required to achieve remission of proteinuria, thus leading to chronic kidney disease with hyalinized lesions. CONCLUSIONS: To the best of our knowledge, this is the first reported case of secondary FSGS by lenvatinib treatment. Renal impairment treated with TKIs is commonly associated with minimal change nephrotic syndrome/FSGS findings, and it is suggested that renal involvement with TKI is different from that with the vascular endothelial growth factor ligand. Overexpression of c-mip due to TKI causes disorders such as podocyte dysregulation and promotion of apoptosis, which cause FSGS. Lenvatinib may result in FSGS by a similar mechanism with another TKI and could cause irreversible renal impairment; therefore caution must be used. It is essential to monitor blood pressure, urinary findings, and the renal function.